PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• Child MeSH
• Adult MeSH
• Gene Fusion * MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Glioma * genetics   drug therapy   pathology   mortality   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Central Nervous System Neoplasms * genetics   mortality   pathology   drug therapy   diagnosis   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Pyrazoles therapeutic use   administration & dosage   MeSH
• Pyrimidines therapeutic use   administration & dosage   MeSH
• Receptor, trkA * genetics   MeSH
• Receptor, trkB genetics   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Oncogene Proteins, Fusion * MeSH
• Protein Kinase Inhibitors MeSH
• larotrectinib MeSH Browser
• Pyrazoles MeSH
• Pyrimidines MeSH
• Receptor, trkA * MeSH
• Receptor, trkB MeSH

Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two patients achieved partial response. Methylation profiling was implemented to further refine the diagnosis and revealed intertumoral heterogeneity in sLGGs. Although 55% of tumors clustered with pilocytic astrocytoma, other rare entities were identified in this patient population. In particular, diffuse leptomeningeal glioneuronal tumors (n = 3) and high-grade astrocytoma with piloid features (n = 1) and pleomorphic xanthoastrocytoma (n = 1) were present. A proportion of tumors (14%) had no match with the current version of the classifier. Complex molecular genetic sLGGs characterization was invaluable to refine diagnosis, which has proven to be essential in such a rare tumor entity. Moreover, identifying a high proportion of drugable targets in sLGGs opened an opportunity for new treatment modalities.

• Keywords
• KIAA1549:BRAF fusion, Low-grade glioma, Methylation profiling, NTRK fusion, Spinal cord,
• MeSH
• Astrocytoma * genetics   MeSH
• Child MeSH
• Genomics MeSH
• Glioma * genetics   pathology   MeSH
• Humans MeSH
• Mitogen-Activated Protein Kinase Kinases MeSH
• Adolescent MeSH
• Spinal Cord Neoplasms * genetics   MeSH
• Brain Neoplasms * genetics   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Mitogen-Activated Protein Kinase Kinases MeSH
• Proto-Oncogene Proteins B-raf MeSH

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

• Keywords
• RAS/MAPK pathway, brain tumor, low-grade glioma, molecular diagnostics, neurooncology, pediatric, risk stratification,
• MeSH
• Child MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Gene Rearrangement * MeSH
• Glioma classification   genetics   pathology   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Mitogen-Activated Protein Kinases genetics   MeSH
• Adolescent MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Brain Neoplasms classification   genetics   pathology   MeSH
• Neurofibromin 1 genetics   MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• ras Proteins genetics   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Gene Expression Profiling MeSH
• DNA Copy Number Variations * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• BRAF-KIAA1549 fusion protein, human MeSH Browser
• Oncogene Proteins, Fusion MeSH
• Mitogen-Activated Protein Kinases MeSH
• Biomarkers, Tumor MeSH
• Neurofibromin 1 MeSH
• NF1 protein, human MeSH Browser
• Proto-Oncogene Proteins B-raf MeSH
• ras Proteins MeSH